This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The early deficits of Alzheimer's disease (AD) likely result from disturbances of synaptic transmission. To understand AD pathogenesis, particularly changes of signal transduction pathways at the synaptic junction, post-synaptic density (PSD) proteins will be prepared from brains of human amyloid precursor protein (hAPP) transgenic mice and nontransgenic controls and used for phosphoproteomics analyses. PSD proteins will be prepared using sucrose density fractionation and then processed and differentially labeled with isotope-coded labeling reagents. The phosphorylated peptides in the sample will be enriched using metal affinity chromatography and both the phospho-enriched and the phospho-depleted portion of the sample will be further fractionated using other liquid chromatography approaches. The differentially labeled, fractionated samples will be analyzed on the ABI QSTAR Elite Q-TOF - LC/MSMS and the relative abundance of the different PSD protein and their phosphorylation levels will be compared between hAPP mice and controls. The whole project will be conducted in a collaborative manner using the phosphoproteomics analysis technical platform developed in the mass spectrometry facility at UCSF.